Drug abuse and depression frequently coexist. The proposed experiments will employ a well-established model of depression to study neurochemical and behavioral changes associated with both drug abuse and depression. The olfactory bulbectomy (OBX) model of depression produces such changes, thus providing a unique opportunity to study the common neurobiological bases of these disorders. OBX produces a behavioral syndrome independent of anosmia that resembles human depression, including loss of circadian activity rhythms, hyperreactivity to stress, decreased meal size, decreased weight gain, and decreased sexual behavior. The OBX syndrome is reversed by chronic but not acute antidepressant treatment. Some of the behavioral changes caused by OBX suggest anhedonia. Lesion-induced plasticity in mesolimbic dopamine systems may mediate this anhedonia. Furthermore, the nature of the dopamine plasticity caused by OBX predicts that bulbectomized rats would be hypersensitive to the stimulant and reinforcing effects of amphetamine. Previous research reveals that OBX increases D1 and D2 receptor density in the olfactory tubercle. Preliminary in situ hybridization experiments from this laboratory indicate that OBX increases levels of D2 receptor and prepro-enkephalin mRNAs in the olfactory tubercle. The olfactory tubercle has previously been implicated in behavioral reinforcement and the actions of drugs of abuse. Experiments will test the hypothesis that bulbectomized rats are more sensitive than intact rats to the stimulant and reinforcing effects of amphetamine because of postsynaptic receptor supersensitivity in the olfactory tubercle. Experiments will also determine whether bulbectomized rats will self-administer amphetamine at higher rates. Brains from all rats in these behavioral studies will be analyzed by in situ hybridization histochemistry, and increases in dopamine receptor and prepro-enkephalin mRNA levels will serve as markers for OBX- induced plasticity in the olfactory tubercle. Preliminary data reveal wide individual differences in amphetamine sensitivity and prepro-enkephalin mRNA plasticity in bulbectomized rats. The ultimate objective of this proposal will therefore be to test the relationship between individual differences in amphetamine-induced behaviors and individual differences in OBX-induced plasticity in the olfactory tubercle. The proposed experiments may reveal a novel mechanism for individual differences in amphetamine sensitivity. The studies may also provide the basis for the first animal model of drug self-administration as a compensatory response to anhedonia.